Theme 5: Experimental infection

Theme 5 of the PROTECT study is conducting experimental infections of both human volunteers and animals with SARS-CoV-2 (the virus that causes COVID-19) to examine how they emit and transmit the virus, particularly in the early stages after infection.

This will answer key questions such as how big a dose of the virus is needed to infect people, and how long afterwards they are most infectious. The UK is the only country in the world conducting such human volunteer studies for COVID-19.

Specific research questions Theme 5 projects aim to address include:

• What is the minimum dose of SARS-CoV-2 required to initiate infection?
• Does the dose of virus that initiates infection affect how ‘shedding’ of the virus from the individual takes place, and the likelihood of onwards transmission?
• During what time following initial infection is most infectious virus emitted?
• How long does the virus remain infectious on the skin?
• Can virus be transferred from skin to skin?
• Are there any genetic markers associated with increased survival of the virus or the generation of airborne viral particles by infected individuals?

The human model

The human volunteers are young, healthy individuals at very low risk of becoming seriously ill from the infection, who stay in a contained and controlled hospital environment for the duration of their participation in the study. During this time, samples are taken from their nose, throat and breath, from the air and surfaces around them, and symptoms are recorded.

Researchers at Imperial College London will use the results to determine the dose of SARS CoV-2 required to infect humans, evaluate the timing of virus shedding in the nose and into the air, and assess the risk of transmission via the air and on surfaces.

Multiple variants of the virus, including the Delta variant, are being used in the study to identify differences in how they transmit. The infection of vaccinated volunteers as well as unvaccinated is also planned.

The hamster model

Results from the human volunteers are compared with those from the animal component of the study, for which researchers at Imperial College London are using hamsters as the best small animal model for SARS-CoV-2 transmission.

We know that the receptors in hamsters that allow the virus to enter the lung, kidney and gastrointestinal tract are very similar to those in humans. We also know that hamsters can be infected by SARS-CoV-2 and are able to shed virus and transmit it through the air.

By infecting hamsters with different doses and variants of the virus, and collecting nasal washes daily after infection, the team can quantify the ‘shedding’ of virus and determine its dynamics. They can also use this model to understand how long after infection SARS-CoV-2 can be transmitted among hamsters.

The ferret model

The ferret model, employed by researchers at the Animal and Plant Health Agency (APHA), is being used to assess if skin can act as a route of transmission to initiate infections.

Ferrets, which provide another useful animal model of mild and asymptomatic human infection, will be exposed to SARS-CoV-2 on pig skin through the oral or nasal route. Infection will be established by regular sampling of the upper respiratory tract and assessment of virus distribution.

The APHA team is also using the ferret model to look at the viability of viral bioaerosols from mild and asymptomatic SARS-CoV-2 infection. Uninfected animals will be co-housed with infected animals, and samples from the air and the upper respiratory tract will be taken to compare quantities of viral RNA. Whole genome sequencing of samples will be carried out to identify if there are specific genetic markers that are related to bioaerosol generation as opposed to contact transmission of the virus.

The pig skin model

As well as the ferret model, APHA researchers are using a pig skin model to replicate human skin. Drops of SARS-CoV-2 variants will be applied to the skin as small droplets or bioaerosols to evaluate survival and transmission of the virus through skin-to-skin contacts.

Animal Research

Imperial College aims to be open about research involving animals. Animal research is strictly regulated by the Home Office and overseen at Imperial College by several ethical committees.

Find out more about animal research at Imperial: www.imperial.ac.uk/research-and-innovation/about-imperial-research/research-integrity/animal-research/

Theme team

Theme lead: Professor Wendy Barclay, Imperial College London

Other partners:

• Animal and Plant Health Agency
• Defence Science and Technology Laboratory
• UK Health Security Agency
• University of Leicester

All research themes

1. Outbreak investigations
2. Transmission modelling
3. Sector-specific studies
4. Tools and methods
6. Knowledge synthesis

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